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MRI Scans, Symptoms and Exacerbation

Magnetic Resonance Imagine with and without contrast dyes.

Normal matter in the brain is grey matter. The white spots or pale areas are lesions in the brain (dead areas) where my own immune system has attacked my Central Nervous System. The areas appear white because of a dye called gadolinium which is administered during the MRI. These lit up areas are currently being attacked and damaged.

My list of ongoing symptoms:

L'hermitte's sign is the term used to describe an electric shock-like sensation which radiates down the back and into the legs (my right Arm) when I flex my neck. This is a sign of nerve damage which shows up when the neck is flexed and the nerve stretched

Fatigue including: intense desire for rest affecting motor and/or sensory nerves and dizziness (not related to the blond of my hair).

Visual disturbance including: optic neuritis (inflammation of the nerve); temporary blindness, and Uhthoff's symptom, the worsening of symptoms with heat or exhaustion. Loss of color and blurring in my left eye.

 

The vestibulo-ocular reflex (VOR) or oculovestibular reflex is a reflex eye movement that stabilizes images on the retina during head movement by producing an eye movement in the direction opposite to head movement, thus preserving the image on the center of the visual field. For example, when the head moves to the right, the eyes move to the left, and vice versa. Since slight head movements are present all the time, the VOR is very important for stabilizing vision: patients whose VOR is impaired find it difficult to read using print, because they cannot stabilize the eyes during small head tremors. The VOR does not depend on visual input and works even in total darkness or when the eyes are closed.

Sensory disturbance including: impairment of sensory perception; loss of feeling, numbness, tingling; different degrees and kinds of pain, including Neuropathic pain mostly in my arm and leg on my right side.

(new) slurred, imprecise or slower speech low volume or weak voice due to respiration problems difficulty with resonance and pitch control, abnormally long pauses between words or syllables of words – this is called ‘scanned speech’. dysarthia, in which the capability to understand, remember words and construct sentences is not lost but the ability to speak clearly becomes affected dysphasia, in which there is a lack of understanding of what is being said and an inability to recall the vocabulary and grammar necessary to build a sentence and the annoyance of losing a word mid-sentence.

Cognitive abnormalities with defects in abstraction, memory, attention and word finding. These symptoms are usually associated with emotional liability and decreased speed on information processing. Thought processes of the brain are interconnected to the conscious areas of the brain via myelinated nerves. There can be problems transporting memories and processing of thoughts creating difficulties with concentration and reasoning. A certain amount of short term memory loss or forgetting to do things is also common. These symptoms show up a great deal when I become overwhelmed and flustered in a new or stressful situation.

Multiple Sclerosis "Hug" or "Girdle" - a spasm-type symptom affecting the muscles around the chest. Feels like something is squeezing me around the ribs. This symptom can be an achy feeling or painful like a Charlie horse around my ribs.

Heat Intolerance or anhidrosis, is a classic symptom of MS where a rise in temperature whether it’s internally or externally, may temporarily increase my symptoms. Being outside in temperatures above 80 degrees will bring my symptoms on within 15 minutes. Sometimes I don't feel symptoms from being over heated until the next day when I wake up with a pseudo exacerbation (short term worsening of symptoms which go away within 24 hours)

Back pain is due to improper seating or incorrect posture while walking. This is called compensation, the body moving in ways to compensate for weakness or lack of balance. Unfortunately the result is often tight muscle and this Musculoskeletal pain.

Muscular spasms or cramps are a common symptom of MS and can be very painful. Leg spasms, for example, often occur during sleep and can cause extreme discomfort and interrupt sleep. So far this has been limited to my legs and toes and doing Yoga stretches every day helps keep this to a minimum.

Neuropathic Pain This is the most common, distressing and intractable of the pain syndromes in MS. This pain is described as constant, boring, burning or tingling intensely. It usually occurs in the legs and feet. Paraesthesias include pins and needles; tingling; shivering; burning pains; feelings of pressure; and areas of skin with heightened sensitivity to touch. The pains associated with these can be aching, throbbing, stabbing, shooting, gnawing, tingling, tightness and numbness. Dysesthesias include burning, aching or girdling around the body.

Exacerbations:

On April 9th I woke up unable to walk without two canes and lots of effort and my voice was soft and husky. I was diagnosed with a new exacerbation and given a three day dose of SoluMedrl by IV with an in home nurse. After two weeks I regained the ability to drive and to walk without assistance. My voice is better as well.

On July 19th I was unable to walk by 4pm without great assistance. I woke up the next morning in the same condition with cognitive problems, stuttering and double vision. I was given a three day dose of SoluMedrl by IV with an in home nurse and recovered within days of the symptoms onset. It still took over two weeks to be able to drive a car again.

On August 4th my MS symptoms returned with jerky movements in my legs when I walked or moved them forward. My hands naturally clamped in a "c" position and were difficult to flatten out without manual help. I started another SoluMedrl IV treatment on the 7th through the 9th with the help of an in-home nurse and finished up with my husband's daily help.

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August 27th 2007

This was the August 2007 MRI report from the Radiologist. There are numerous, approximately 20-25, white matter lesions within the periventricular white matter Bilaterally. The overall distribution has not significantly changed and the overall number appears to be similar; however, the size may have minimally increased and the intensity of the lesions on FLAIR imaging has increased in signal, and suggesting progression. The largest lesion measures 9.5mm.

Dr. Singer and Dr. Kaplan have both suggested a change from Copaxone to the use of a Beta Interferon, Tysabre or Navantrone.

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September 29th 2007

Symptoms returned again, quickly. My husband asked that I try a new neurologist, one I had seen for a second opinion, Dr. Swartzman with the Neurology group of Kansas City. I was placed on 7 days of IV Solu Medrl and my daily shots of Copaxone were replaced with tri-weekly shots of Rebif.

I am in remission again and I hope to stay this way with the new medication.

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November 18th 2007

Was hospitalized with MS symptoms ranging from numbness in Hands, feet and legs, as well as softening of voice and slurring of words. I am on another 7 days of SoluMedrl 1,000mg.

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January 6th 2008

The exacerbation started with memory problems and weakness. Robert was in Boston and I waited until Thursday to go to the Doctor. By then I was walking with two canes and not able to drive or function at all. That afternoon at 3pm I had my IV Solumedrl administered. Dr. Swartzman said he is very concerned about my frequency of excacerbations and I have two MRIs scheduled for next week and if they show change I will be placed on a stronger medication call Tysabre. Today I walk around the house without a cane and I feel better. My legs are buzzy and my neck hurts which means feeling is coming back.

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April 5th, 2008

Week before the exacerbation I was having sinus issues, dizziness and nausea while driving or playing PS/2 games with Rory. Saturday woke up and found it hard to walk. I had numbness in my hand to the wrist and numbness in my feet and legs up to my buttocks. As the day wore on lost ability to move one leg in front of the other. 11am went the emergency room. 3pm admitted to hospital for solumedral treatments, potassium and magnesium treatments and watch my thyroid levels which were too high. I was discharged the next day after begging Dr. Atkins to get a hold of my at home infusion service to complete the rest of the solumedrl treatments.

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May 27th, 2008

I started Tysabri infusions at 9am. I had a bit of skin flushing and dizziness when the infusion stopped. I experienced fatigue, joint soreness and a bad headache for a couple days afterwards. One week later I am feeling very well. My next infusion is the 26th of June. 3 weeks after the IV I started getting infections. Ihad a bladder infection, double ear infection with sinus and sore throat. My asthma started getting worse and I was given treatments of steroids and Xopenex. Dr. Swartzman was concerned that this was a side effect of the Tysabri.

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July 15th, 2008

My second infusion of Tysabri, July 15th at 9am. I did not suffer any infections this time, just fatigue and joint pain for a day or two.

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August 6th 2008

My MS symptoms started Friday August first with not being able to walk and fatigue. I have numbness to the knee on my right side and to the ankle on my left. My hands are numb on and off during the day. My left eye does not pick up white whites and jitters (or darts) back and forth when I am under a great deal of stress. I started Solumedrl today at noon and I have taking a 5 day course after seeing Dr. Swartzman and his prescribing it for the week.

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August 12th, 2008

My third infusion of Tysabri, and it has thrown my blood sugars off a bit.

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September 8th, 2008

My fourth infusion of Tysabri, a batch of UTIs only.

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October 4th-14th, 2008

I had very bad MS Exacerbation on October 4th, 2008. I woke up fine and made the kid's beds. Took a shower and was laying down watching Oswald with Annie. I got up and could not walk. I fell on the floor in a heap. I asked Robert to take me to the hospital. I was up in Surgical care until 7th and I was moved down into Rehabilitation that day. I had a room alone and I was not allow to get up or go to the bathroom with out a nurse.

In the Hospital my symptom became worse with the flu. The right side was entirely and completely numb. I could not feel texture and my face was drooping. I was having trouble swallowing and a swallow study was done. My asthma also kicked in pretty good.

The grandparents having taken care of the kids while Rob went to Florida. I was very afraid and stressed. I almost left against medical advice on Friday night, but got a 2 hour pass and finished my physical therapy through the last days alone.

I was givem 5 days of Solumedrl with no taper. I missed my 5th Infusion of Tysabri.

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November 3rd

5th Tysabri infusion at 9am.

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December 1st

6th Tysabri Infision and Wednesday I have an MRI to determine if thye are working.

The news was not the best. There are news lesions and new areas of activity where the Blood brain barrier has been compromised. This shows up as white spots on the grey matter in the MRI.

 

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January 11th 2009

Went to see Dr. Swartzman for increased numbness on right side and eye problems. I was given a 10 day 80mg to 10mg taper of Prednisone. This comes after nuberous infections of the sinuses and gums.

Pathophysiology of multiple sclerosis

From Wikipedia, the free encyclopedia

Multiple sclerosis is a disease in which the myelin (a fatty substance which covers the axons of nerve cells, important for proper nerve conduction) degenerates. At least five characteristics are present in CNS tissues of MS patients: Inflammation beyond classical white matter lesions, Intrathecal Ig production with oligoclonal bands, An environment fostering immune cell persistence, Follicle-like aggregates in the meninges and a disruption of the blood-brain barrier also outside of active lesions[1].

Apart of the usually known white matter demyelination, also the cortex and deep gray matter (GM) nuclei are affected, together with diffuse injury of the normal-appearing white matter.[2]. GM atrophy is independent of the MS lesions and is associated with physical disability, fatigue, and cognitive impairment in MS[3] Contents

Normally, there is a tight barrier between the blood and brain, called the blood-brain barrier (BBB), built up of endothelial cells lining the blood vessel walls. It should prevent the passage of antibodies through it, but in MS patients it does not work. For unknown reasons leaks appear in the blood-brain barrier. These leaks, in turn, cause a number of other damaging effects such as swelling, activation of macrophages, and more activation of cytokines and other proteins such as matrix metalloproteinases which are destructive[7].

The final result is destruction of myelin, called demyelination. Whether BBB dysfunction is the cause or the consequence of MS[8] is still disputed,because activated T-Cells can cross a healthy BBB when they express adhesion proteins [9] A deficiency of uric acid has been implicated in this process. Uric acid added in physiological concentrations (i.e. achieving normal concentrations) is therapeutic in MS by preventing the breakdown of the blood brain barrier through inactivation of peroxynitrite.[10] The low level of uric acid found in MS victims is manifestedly causative rather than a consequence of tissue damage in the white matter lesions,[11] but not in the grey matter lesions.[12]. Besides, uric acid levels are lower during relapses[13].

The axons themselves can also be damaged by the attacks.[14] Often, the brain is able to compensate for some of this damage, due to an ability called neuroplasticity. MS symptoms develop as the cumulative result of multiple lesions in the brain and spinal cord. This is why symptoms can vary greatly between different individuals, depending on where their lesions occur. Repair processes, called remyelination, also play an important role in MS.

Remyelination is one of the reasons why, especially in early phases of the disease, symptoms tend to decrease or disappear temporarily. Nevertheless, nerve damage and irreversible loss of neurons occur early in MS. Proton magnetic resonance spectroscopy has shown that there is widespread neuronal loss even at the onset of MS, largely unrelated to inflammation.[15] The oligodendrocytes that originally formed a myelin sheath cannot completely rebuild a destroyed myelin sheath. However, the central nervous system can recruit oligodendrocyte stem cells capable of proliferation and migration and differentiation into mature myelinating oligodendrocytes. The newly-formed myelin sheaths are thinner and often not as effective as the original ones. Repeated attacks lead to successively fewer effective remyelinations, until a scar-like plaque is built up around the damaged axons. Under laboratory conditions, stem cells are quite capable of proliferating and differentiating into remyelinating oligodendrocytes; it is therefore suspected that inflammatory conditions or axonal damage somehow inhibit stem cell proliferation and differentiation in affected areas[16]

Blood-brain barrier disruption A healthy blood-brain barrier shouldn't allow T-cells to enter the nervous system. Therefore BBB disruption has always been considered one of the early problems in the MS lesions. Recently it has been found that this happens even in non-enhancing lesions[17], and it has been found with iron oxide nanoparticles how macrophages produce the BBB disruption [18]. The BBB breakdown is responsible for monocyte infiltration and inflammation in the brain[19].

Normally, gadolinium enhancement is used to show BBB disruption on MRIs[20]. Abnormal tight junctions are present in both SPMS and PPMS. They appear in active white matter lesions, and gray matter in SPMS. They persist in inactive lesions, particularly in PPMS[21] A special role is played by Matrix metalloproteinases. These are a group of proteases that increase T-cells permeability of the blood-brain barrier, specially in the case of MMP-9[22], and are supposed to be related to the mechanism of action of interferons[23], Apart from that, activated T-Cells can cross a healthy BBB when they express adhesion proteins.[9] In particular, one of these adhesion proteins involved is ALCAM (Activated Leukocyte Cell Adhesion Molecule, also called CD166), and is under study as therapeutic target[24]. Other protein also involved is CXCL12[25], which is found also in brain biopsies of inflammatory elements[26], and which could be related to the behavior of CXCL13 under methylprednisolone therapy[27]. Haemodynamics of the lesions have been measured and distortion has been found related to plaque distribution[28]. It was measured through transcranial color-coded duplex sonography (TCCS). The permeability of two cytokines, IL15 and LPS, could be involved in the BBB breakdown[29]. Haemodynamics of the rest of the blood stream is also abnormal in MS patients[30] The importance of vascular misbehaviour in MS pathogenesis has been confirmed by seven-tesla MRI[31].

A number of histopathologic studies have provided evidence of vascular occlusion in MS, suggesting that there is possible primary vascular injury in MS lesions as well as the NAWM and NAGM[32]. Monocyte migration and LFA-1-mediated attachment to brain microvascular endothelia is regulated by SDF-1alpha through Lyn kinase[33] Nevertheless, the idea of the BBB disruption as primary trigger event in lesion development has been disputed and its have been proposed that previous changes in White Matter structure are a previous trigger[34]. [edit] Spinal cord damage Cervical spinal cord has been found to be affected by MS even without attacks, and damage correlates with disability[35]. In RRMS, cervical spinal cord activity is enhanced, to compensate for the damage of other tissues[36]. Progressive tissue loss and injury occur in the cervical cord of MS patients. These two components of cord damage are not interrelated, suggesting that a multiparametric MRI approach is needed to get estimates of such a damage.

MS cord pathology is independent of brain changes, develops at different rates according to disease phenotype, and is associated to medium-term disability accrual[37]. Spinal cord presents grey matter lesions, that can be confirmed post-mortem and by high field MR imaging.

Spinal cord grey matter lesions may be detected on MRI more readily than GM lesions in the brain, making the cord a promising site to study the grey matter demyelination[38]. [edit] Retina and optic nerve damage There is axonal loss in the retina and optic nerve, which can be meassured by Optical coherence tomography[39] or by Scanning laser polarimetry[40]. This measure can be used to predict disease activity.[41] The retina is unique within the CNS in that it contains axons and glia but no myelin, and it is, therefore, an ideal structure within which to visualize the processes of neurodegeneration[42]. Tissue-bound IgG was demonstrated on retinal ganglion cells in six of seven multiple sclerosis cases but not in controls[43]. Uveitis and retinal phlebitis are manifestations of MS. Trypsin digestion with microscopic examination is a method of testing for phlebitis and the frequency found in this series is higher than in others. These lesions are similar to the perivenular cuffing that occurs in the central nervous system in MS[44].

Brain tissues abnormalities Using several texture analysis technologies it is possible classify the white matter MRI areas in three: normal, normal-appearing and lesions[45] [edit] Lesion distribution Using high field MRI system, with several variants several areas show lesions, and can be spacially classified in infratentorial, callosal, juxtacortical, periventricular, and other white matter areas[46]. Other authors simplify this in three regions: intracortical, mixed gray-white matter, and juxtacortical[47]. Others classify them as hippocampal, cortical, and WM lesions[48], and finally, others give seven areas: intracortical, mixed white matter-gray matter, juxtacortical, deep gray matter, periventricular white matter, deep white matter, and infratentorial lesions[49] Post-mortem authopsy reveal that gray matter demyelination occurs in the motor cortex, cingulate gyrus, cerebellum, thalamus and spinal cord[50].

Cortical lesions have been observed specially in people with SPMS but they also appear in RRMS and clinically isolated syndrome. They are more frequent in men than in women[51] and they can partly explain cognitive deficits. It is known that two parameters of the cortical lesions, fractional anisotropy (FA) and mean diffusivity (MD), are higher in patients than in controls[52]. They are larger in SPMS than in RRMS and most of them remain unchanged for short follow-up periods. They do not spread into the subcortical white matter and never show gadolinium enhancement. Over a one-year period, CLs can increase their number and size in a relevant proportion of MS patients, without spreading into the subcortical white matter or showing inflammatory features similar to those of white matter lesions.[53]

New methods of MRI allow us to get a better classification of the lesions. Recently MPRAGE MRI has shown better results than PSIR and DIR for gray matter lesions[54]. [edit] Normal appearing brain tissues Brain tissues with normal aspect under normal MRI (Normal appearing white matter, NAWM and normal appearing grey matter, NAGM) show several abnormalities under diffusion tensor MRI or Magnetic Transfer MRI. This is currently an active field of research with no definitive results, but it seems that these two technologies are complementary[55]. These abnormalities can be studied with special MRI techniques like Magnetization transfer multi-echo T(2) relaxation. Subjects with Long-T(2) lesions had a significantly longer disease duration than subjects without this lesion subtype[56].

It has been found that grey matter injury correlates with disability[57] and that there is high oxidative stress in lesions, even in the old ones. [58]. Water diffusivity is higher in all NAWM regions, deep gray matter regions, and some cortical gray matter region of MS patients than normal controls[59]. Post-mortem studies over NAWM and NAGM areas show several biochemical alterations, like increased protein carbonylation and high levels of Glial fibrillary acidic protein (GFAP), which in NAGM areas comes together with higher than normal concentration of protein carbonyls, suggesting reduced levels of antioxidants and the presence of small lesions[60]. The amount of interneuronal Parvalbumin is lower than normal in brain's motor cortex areas[61].

Citrullination appears in SPMS[62]. It seems that a defect of sphingolipid metabolism modifies the properties of normal appearing white matter[63]. Related to these, peptidylarginine deiminase 2 is increased in patients with MS, and is related to arginine de-imination[64]. NAWM shows a decreased perfusion which does not appear to be secondary to axonal loss. The reduced perfusion of the NAWM in MS might be caused by a widespread astrocyte dysfunction, possibly related to a deficiency in astrocytic beta(2)-adrenergic receptors and a reduced formation of cAMP, resulting in a reduced uptake of K(+) at the nodes of Ranvier and a reduced release of K(+) in the perivascular spaces[65]. White matter lesions appear in NAWM areas[66], and their behavior can be predicted by MRI parameters as MTR (magnetization transfer ratio)[67][68]. This MTR parameter is related to axonal density[69]. Gray matter tissue damage dominates the pathological process as MS progresses, and underlies neurological disability. Imaging correlates of gray matter atrophy indicate that mechanisms differ in RRMS and SPMS[70].

Normal brain tissues It has been stablished that myelin basic protein (MBP) from multiple sclerosis (MS) patients contains lower levels of phosphorylation at Thr97 than normal individuals[71].

Neural and axonal damage The axons of the neurons are damaged probably by B-Cells[72], though currently no relationship has been established with the relapses or the attacks[73]. It seems that this damage is primray target of the immune system, i.e. not secondary damage after attacks against myelin[74] A relationship between neural damage and N-Acetyl-Aspartate concentration has been established, and this could lead to new methods for early MS diagnostic through magnetic resonance spectroscopy[75] Axonal degeneration at CNS can be estimated by N-acetylaspartate to creatine (NAA/Cr) ratio, both measured by with proton magnetic resonance spectroscopy[76].

Blood and CSF abnormalities Since long time ago it is known that glutamate is present at higher levels in CSF during relapses[77] compared to healthy subjects and to MS patients before relapses. Also a specific MS protein has been found in CSF, chromogranin A, possibly related to axonal degeneration. It appears together with clusterin and complement C3, markers of complement-mediated inflammatory reactions[78]. Also Fibroblast growth factor-2 appear higher at CSF[79]. Blood serum also shows abnormalities. Creatine and Uric acid levels are lower than normal, at least in women[80]. Ex vivo CD4(+) T cells isolated from the circulation show a wrong TIM-3 (Immunoregulation) behavior[81], and relapses are associated with CD8(+) T Cells[82].There is a set of differentially expressed genes between MS and healthy subjects in peripheral blood T cells from clinically active MS patients.

There are also differences between acute relapses and complete remissions[83]. Platelets are known to have abnormal high levels[84]. MS patients are also known to be CD46 defective, and this leads to Interleukin-10 (IL-10) deficiency, being this involved in the inflammatory reactions[85]. Levels of IL-2, IL-10, and GM-CSF are lower in MS females than normal. IL6 is higher instead. These findings do not apply to men[86]. This IL-10 interleukin could be related to the mechanism of action of methylprednisolone, together with CCL2. Interleukin IL-12 is also known to be associated with relapses, but this is unlikely to be related to the response to steroids[87] Kallikreins are found in serum and are associated with secondary progressive stage[88].

There is evidence of Apoptosis-related molecules in blood and they are related to disease activity[89]. B cells in CSF appear, and they correlate with early brain inflammation[90]. Varicella-zoster virus particles have been found in CSF of patients during relapses, but this particles are virtually absent during remissions[91]. Plasma Cells in the cerebrospinal fluid of MS patients could also be to blame, because they have been found to produce myelin-specific antibodies[92]. There is also an overexpression of IgG-free kappa light chain protein in both CIS and RR-MS patients, compared with control subjects, together with an increased expression of an isoforms of apolipoprotein E in RR-MS[93]. Expression of some specific proteins in circulating CD4+ T cells is a risk factor for conversion from CIS to clinically defined multiple sclerosis[94]. Recently, unique autoantibody patterns that distinguish RRMS, secondary progressive (SPMS), and primary progressive (PPMS) have been found, based on up- and down-regulation of CNS antigens [95], tested by microarrays.

In particular, RRMS is characterized by autoantibodies to heat shock proteins that were not observed in PPMS or SPMS. These antibodies patterns can be used to monitor disease progression[96]. [edit] Heterogeneity of the disease Multiple sclerosis has been reported to be heterogeneus in its behavior, in its underlaying mechanisms and recently also in its response to medication[97] [edit] Demyelination patterns Also known as Lassmann patterns[98], it is believed that they may correlate with differences in disease type and prognosis, and perhaps with different responses to treatment. This report suggests that there may be several types of MS with different immune-related causes, and that MS may be a family of several diseases. The four identified patterns are [7]:

Pattern I The scar presents T-cells and macrophages around blood vessels, with preservation of oligodendrocytes, but no signs of complement system activation.[99]

Pattern II The scar presents T-cells and macrophages around blood vessels, with preservation of oligodendrocytes, as before, but also signs of complement system activation can be found.[100]

Pattern III The scars are diffuse with inflammation, distal oligodendrogliopathy and microglial activation. There is also loss of myelin associated glycoprotein (MAG). The scars do not surround the blood vessels, and in fact, a rim of preserved myelin appears around the vessels. There is evidence of partial remyelinization and oligodendrocyte apoptosis.

Pattern IV The scar presents sharp borders and oligodendrocyte degeneration, with a rim of normal appearing white matter. There is a lack of oligodendrocytes in the center of the scar. There is no complement activation or MAG loss.

The meaning of this fact is controversial. For some investigation teams it means that MS is a heterogeneous disease. Others maintain that the shape of the scars can change with time from one type to other and this could be a marker of the disease evolution. Anyway, the heterogeneity could be true only for the early stage of the disease[101]. Some lesions present mitocondrial defects that could distinguish types of lesions[102]. Currently antibodies to lipids and peptides in sera, detected by microarrays, can be used as markers of the pathological subtype given by brain biopsy[103].

Correlation with clinical courses No definitive relationship between these patterns and the clinical subtypes has been established by now, but some relations have been established. All the cases with PPMS (primary progressive) had pattern IV (oligodendrocyte degeneration) in the original study [104] and nobody with RRMS was found with this pattern. Balo concentric sclerosis lesions have been classified as pattern III (distal oligodendrogliopathy)[105]. Neuromyelitis optica was associated with pattern II (complement mediated demyelination), though they show a perivascular distribution, at difference from MS pattern II lesions[106].

Correlation with MRI and MRS findings The researchers are attempting this with magnetic resonance images to confirm their initial findings of different patterns of immune pathology and any evidence of possible disease “sub-types” of underlying pathologies. It is possible that such “sub-types” of MS may evolve differently over time and may respond differently to the same therapies. Ultimately investigators could identify which individuals would do best with which treatments. It seems that Pulsed magnetization transfer imaging,[107] diffusion Tensor MRI,[108] and VCAM-1 enhanced MRI[109] could be able to show the pathological differences of these patterns. Together with MRI, magnetic resonance spectroscopy will allow in the future to see the biochemical composition of the lesions.

Correlation with CSF findings Teams in Oxford and Germany,[110]found correlation with CSF and progression in November 2001, and hypotheses have been made suggesting correlation between CSF findings and pathophysiological patterns[111]. In particular, B-cell to monocyte ratio looks promising. The anti-MOG antibody has been investigated but no utility as biomarker has been found [112], though this is disputed[113]. High levels of anti-nuclear antibodies are found normally in patients with MS. Antibodies against Neurofascin–186 could be involved in a subtype of MS [114]

Response to therapy It is known that 30% of MS patients are non-responsive to Beta interferon[115]. The heterogeneous response to therapy can support the idea of hetherogeneous aetiology. It has also been shown that IFN receptors and interleukins in blood serum predicts response to IFN therapy[116][117], and interleukins IL12/IL10 ratio has been proposed as marker of clinical course[118].

Besides: Pattern II lesions patients are responsive to plasmapheresis, while others are not.[119][120] The subtype associated with macrophage activation, T cell infiltration and expression of inflammatory mediator molecules may be most likely responsive to immunomodulation with interferon-beta or glatiramer acetate.[121] People non-responsive to interferons are the most responsive to Copaxone [8][122] In general, people non-responsive to a treatment is more responsive to other [123], and changing therapy can be effective[124].

There are genetic differences between responders and not responders.[125] Though the article points to heterogeneous metabolic reactions to interferons instead of disease heterogeneity, it has been shown that most genetic differences are not related to interferon behavior[126] [edit] Subgroups by molecular biomarkers Differences have been found between the proteines expressed by patients and healthy subjects, and between attacks and remissions. Using DNA microarray technology groups of molecular biomarkers can be established[127]. [edit] Pubertal and pediatric MS MS cases are rare before puberty, but they can happen. Whether they constitute a separate disease is still an open subject. Anyway, even this pubertal MS could be more than one disease, because early-onset and late-onset have different demyelination patterns[128]

Discovery The National MS society launched The Lesion Project to classify the different lesion patterns of MS. Claudia F. Lucchinetti, MD from Mayo Clinic and collaborators from the U.S., Germany and Austria were chosen to conduct this study for their previous contributions in this area. They have amassed a large collection of tissue samples from people with MS through brain biopsies or autopsy. Claudia Lucchinetti was appointed director of this project. The group has reported promising findings on samples from 83 cases. They found four types of lesions, which differed in immune system activity. Within each person, all lesions were the same, but lesions differed from person to person. The first article about pathophysiological heterogeneity was in 1996,[129] and has been confirmed later by several teams. Four different damage patterns have been identified by her team in the scars of the brain tissue.

Understanding lesion patterns can provide information about differences in disease between individuals and enable doctors to make more accurate treatment decisions. According to one of the researchers involved in the original research "Two patterns (I and II) showed close similarities to T-cell-mediated or T-cell plus antibody-mediated autoimmune encephalomyelitis, respectively.

The other patterns (III and IV) were highly suggestive of a primary oligodendrocyte dystrophy, reminiscent of virus- or toxin-induced demyelination rather than autoimmunity." Apart of this, recent achievements in related diseases, like neuromyelitis optica have shown that varieties previously suspected different from MS are in fact different diseases. In neuromyelitis optica, a team was able to identify a protein of the neurons, Aquaporin 4 as the target of the immune attack. This has been the first time that the attack mechanisme of a type of MS has been identified [130]. The investigators are now trying to identify the types of cells involved with tissue destruction, and examining clinical characteristics of the individuals from whom these tissues were taken. The MS Lesion Project has just been renewed with a commitment of $1.2 million for three years. It is now part of the Promise 2010 campaign.

Research Until recently, most of the data available came from post-mortem brain samples and animal models of the disease, such as the experimental autoimmune encephalomyelitis (EAE), an autoimmune disease that can be induced in rodents, and which is considered a possible animal model for multiple sclerosis.[131] However, since 1998 brain biopsies apart from the post-mortem samples were used, allowing researchers to identify the previous four different damage patterns in the scars of the brain.[132]

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References

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^ Lassmann H, Brück W, Lucchinetti CF (April 2007). "The immunopathology of multiple sclerosis: an overview". Brain Pathol. 17 (2): 210–8. doi:10.1111/j.1750-3639.2007.00064.x.

^ Pirko I, Lucchinetti CF, Sriram S, Bakshi R (February 2007). "Gray matter involvement in multiple sclerosis". Neurology 68 (9): 634–42. doi:10.1212/01.wnl.0000250267.85698.7a.

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^ Patients' Multiple Sclerosis Lesion Type Dictates Effective Treatment

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